Platform For Translational Research Research Articles

PlatformTM, a standards-based data custodianship platform for translational medicine research

Biomedical informatics has traditionally adopted a linear view of the informatics process (collect, store and analyse) in translational medicine (TM) studies; focusing primarily on the challenges in data integration and analysis. However, a data management challenge presents itself with the new lifecycle view of data emphasized by the recent calls for data re-use, long term data preservation, and data sharing. There is currently a lack of dedicated infrastructure focused on the ‘manageability’ of the data lifecycle in TM research between data collection and analysis. Current community efforts towards establishing a culture for open science prompt the creation of a data custodianship environment for management of TM data assets to support data reuse and reproducibility of research results. Here we present the development of a lifecycle-based methodology to create a metadata management framework based on community driven standards for standardisation, consolidation and integration of TM research data. Based on this framework, we also present the development of a new platform (PlatformTM) focused on managing the lifecycle for translational research data assets.

Abstract 1067: A patient-derived xenograft (PDX) platform for cancer translational, precision medicine and health disparity research

Abstract Introduction and Objective: This purpose of this program is to develop and characterize PDXs from multiple organ sites and patients of multiple ethnic backgrounds, and to make these resources available to the scientific community for translational, precision medicine, and health disparity research. Methods: PDXs were directly developed from patient cancer specimens, molecularly characterized with next-generation sequencing, and annotated with clinical information. Various aspects of its applications were tested. Results: UC Davis, working in collaboration with The Jackson Laboratory (JAX), has developed PDX models, reflecting a wide range of tumor types, from 150 of our patients. Each of these models is annotated with clinical and genomic information. The fidelity of these PDXs was validated by the retention of histopathological features and the conservation of genetic aberrations (i.e., 92-97%) of the original patient tumors in bladder cancer PDXs tested. Extensive preclinical studies showed that these PDXs could potentially be used to screen multiple therapeutic agents simultaneously to identify the most efficacious drugs or drug combinations, re-purpose FDA-approved drugs, decipher the mechanisms of primary resistance, decrypt the mechanisms of secondary resistance, guide drug development, and identify biomarkers. For drug repurposing, the EGFR/ERBB2 dual inhibitor lapatinib effectively prolonged the overall survival (OS) of mice carrying ERBB2+ bladder cancer PDXs from 18.4 days to 25.4 days (p=0.007). For screening of targeted therapy in a PDX carrying PI3K, ERBB2 and Src alterations, only a PI3K inhibitor (BEZ235) prolonged the OS (p<0.0001) while lapatinib and a Src inhibitor ponatinib had no effect. For biomarker development, DNA adduct levels correlated with cancer response to alkylating agents and this project has already been translated into a clinical trial. For determination of the mechanisms of secondary resistance, loss of tumor suppressor gene LSP1 expression was associated with secondary resistance to an inhibitor of the PI3K pathway which is commonly mutated in many cancers. With the support of the Minority PDX Development and Trial Center (M-PDTC) U54 grant, UC Davis will continue to establish over 200 PDX models from bladder, lung squamous cell, gastric and hepatocellular carcinoma, with >60% of the specimens coming from minority patients, for health disparity research. Conclusions: PDXs have great potential for cancer translational, precision medicine and health disparity research. The NCI-funded U54 center with minority PDXs is open for collaboration through the PDX Development and Trial Centers Research Network (PDXNet). Citation Format: Chong-Xian Pan, Hongyong Zhang, Ai-Hong Ma, Shuxiong Zeng, Maike Zimmermann, Clifford Tepper, Paul Henderson, Luis Carvajal-Carmona, Regina Gandour-Edwards, Moon Chen, Susan Airhart, Ralph de Vere Whtie. A patient-derived xenograft (PDX) platform for cancer translational, precision medicine and health disparity research [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1067.

Persistent primary cytomegalovirus infection in a kidney transplant recipient: Multi-drug resistant and compartmentalized infection leading to graft loss

Cytomegalovirus (CMV) is one of the most common opportunistic infections after transplantation. To prevent CMV infections, universal prophylaxis and pre-emptive therapy with ganciclovir or its prodrug valganciclovir is applied. However, prolonged antiviral therapy may result in drug-resistance emergence. We describe a case of a 43-year-old CMV-seronegative patient who underwent kidney transplantation from a CMV-seropositive donor and developed CMV disease despite valganciclovir prophylaxis. CMV viral load increased even though valgangiclovir dose was augmented and immunosuppressive therapy reduced. CMV genotyping revealed mutations in the viral UL97 protein kinase, explaining ganciclovir-resistant CMV infection. The viral load failed to respond to foscavir, cidofovir and CMV-neutralizing immunoglobulins. Kidney allograft dysfunction developed 3 months post-transplantation with a histopathologic diagnosis of CMV nephropathy and potentially concomitant T-cell mediated rejection. A transplantectomy was performed on day 164 post-transplantation since the patient had uncontrollable CMV disease associated with a circulating multidrug-resistant DNA polymerase-mutant virus. Detailed monitoring in this patient demonstrated hallmarks of complicated CMV disease: (i) relatively rapid evolution of drug-resistant CMV mutants in the setting of persistent high blood viral loads, (ii) emergence of viral drug-resistance linked to acute graft rejection, (iii) transient and, thereafter, lack of response to various anti-CMV treatments, (iv) compartmentalization and heterogeneity of CMV viral populations, (v) possible differential ability of viral mutants to cause disease in the graft, and (vi) detection of minor viral variants by next generation sequencing. Translational research platforms that provide rapid molecular genotyping for detection of CMV drug-resistance are essential in guiding CMV disease management in high-risk transplant recipients.

Establishment of porcine and human expanded potential stem cells.

We recently derived mouse expanded potential stem cells (EPSCs) from individual blastomeres by inhibiting the critical molecular pathways that predispose their differentiation. EPSCs had enriched molecular signatures of blastomeres and possessed developmental potency for all embryonic and extra-embryonic cell lineages. Here, we report the derivation of porcine EPSCs, which express key pluripotency genes, are genetically stable, permit genome editing, differentiate to derivatives of the three germ layers in chimeras and produce primordial germ cell-like cells in vitro. Under similar conditions, human embryonic stem cells and induced pluripotent stem cells can be converted, or somatic cells directly reprogrammed, to EPSCs that display the molecular and functional attributes reminiscent of porcine EPSCs. Importantly, trophoblast stem-cell-like cells can be generated from both human and porcine EPSCs. Our pathway-inhibition paradigm thus opens an avenue for generating mammalian pluripotent stem cells, and EPSCs present a unique cellular platform for translational research in biotechnology and regenerative medicine.

A large collection of integrated genomically characterized patient-derived xenografts highlighting the heterogeneity of triple-negative breast cancer.

Triple-negative breast cancer (TNBC) represents 10% of all breast cancers and is a very heterogeneous disease. Globally, women with TNBC have a poor prognosis, and the development of effective targeted therapies remains a real challenge. Patient-derived xenografts (PDX) are clinically relevant models that have emerged as important tools for the analysis of drug activity and predictive biomarker discovery. The purpose of this work was to analyze the molecular heterogeneity of a large panel of TNBC PDX (n = 61) in order to test targeted therapies and identify biomarkers of response. At the gene expression level, TNBC PDX represent all of the various TNBC subtypes identified by the Lehmann classification except for immunomodulatory subtype, which is underrepresented in PDX. NGS and copy number data showed a similar diversity of significantly mutated gene and somatic copy number alteration in PDX and the Cancer Genome Atlas TNBC patients. The genes most commonly altered were TP53 and oncogenes and tumor suppressors of the PI3K/AKT/mTOR and MAPK pathways. PDX showed similar morphology and immunohistochemistry markers to those of the original tumors. Efficacy experiments with PI3K and MAPK inhibitor monotherapy or combination therapy showed an antitumor activity in PDX carrying genomic mutations of PIK3CA and NRAS genes. TNBC PDX reproduce the molecular heterogeneity of TNBC patients. This large collection of PDX is a clinically relevant platform for drug testing, biomarker discovery and translational research.

Myocardial Slices: an Intermediate Complexity Platform for Translational Cardiovascular Research

Myocardial slices, also known as “cardiac tissue slices” or “organotypic heart slices,” are ultrathin (100–400 μm) slices of living adult ventricular myocardium prepared using a high-precision vibratome. They are a model of intermediate complexity as they retain the native multicellularity, architecture, and physiology of the heart, while their thinness ensures adequate oxygen and metabolic substrate diffusion in vitro. Myocardial slices can be produced from a variety of animal models and human biopsies, thus providing a representative human in vitro platform for translational cardiovascular research. In this review, we compare myocardial slices to other in vitro models and highlight some of the unique advantages provided by this platform. Additionally, we discuss the work performed in our laboratory to optimize myocardial slice preparation methodology, which resulted in highly viable myocardial slices from both large and small mammalian hearts with only 2–3% cardiomyocyte damage and preserved structure and function. Applications of myocardial slices span both basic and translational cardiovascular science. Our laboratory has utilized myocardial slices for the investigation of cardiac multicellularity, visualizing 3D collagen distribution and micro/macrovascular networks using tissue clearing protocols and investigating the effects of novel conductive biomaterials on cardiac physiology. Myocardial slices have been widely used for pharmacological testing. Finally, the current challenges and future directions for the technology are discussed.

Translational research platform for intelligent deep brain stimulation

Deep Brain Stimulation (DBS) is a widely-used and effective therapeutic strategy for Parkinson’s Disease (PD). However, many previous studies observed non-significant effects and/or reported severe side effects of DBS. One possible reason is that the continuous DBS with a constant simulation pattern cannot provide an appropriate modulation to the neural network, of which the dynamics switch rapidly between different neural states and changes gradually along with the progression of disease. A novel intelligent DBS with neural feedbacks holds great promise to improve the effects and efficiency of DBS.

Establishment of the Seoul National University Prospectively Enrolled Registry for Genitourinary Cancer (SUPER-GUC): A prospective, multidisciplinary, bio-bank linked cohort and research platform.

PurposeTo establish a prospective, comprehensive, multidisciplinary, bio-bank linked genitourinary cancer cohort based on standard real practice.Materials and MethodsWe established the Seoul National University Prospectively Enrolled Registry for Genitourinary Cancer (SUPER-GUC), a prospective cohort clinical database and bio-specimen repository system for prostate cancer (SUPER-PC), renal cell carcinoma (SUPER-RCC), and urothelial cancer (SUPER-UC) at a high-volume, tertiary institution. Each cohort consists of several sub-cohorts based on treatment or disease status. Detailed longitudinal clinical information, and general and disease specific patient-reported outcomes are captured. We use the same evaluation format and questionnaires for all participating departments. Patients' blood, urine, tumor, and normal tissues are collected. The number of registered patients and their basic characteristics are summarized. For the surgical sub-cohort, study participation, bio-specimen, and tissue banking rates are analyzed.ResultsSince March 2016, 11 sub-cohorts for all disease statuses have been opened, ranging from low-risk localized to metastatic disease. SUPER-PC, SUPER-RCC, and SUPER-UC enrolled 929, 796, and 1,221 patients, respectively. Study participation, bio-sampling, and fresh frozen tumor banking rates of surgical sub-cohorts were 89.0% to 93.1%, 91.2% to 99.1%, and 56.9% to 79.1%, respectively.ConclusionsSUPER-GUC is a study platform for comparative outcome, quality-of-life, and translational (genetics, biomarkers) research for genitourinary cancer.

Will liquid biopsies improve outcomes for patients with small-cell lung cancer?

Small-cell lung cancer (SCLC) is an aggressive tumour that seeds metastases early with dismal outcomes. As expected from a disease that is closely associated with smoking, mutation burden in SCLC is high. Intratumoral and intertumoral heterogeneity is a substantial obstacle to successful treatment and the SCLC genomic landscape reveals few targets that are readily druggable. Chemotherapy elicits responses in most patients with SCLC, but their effects are short lived. Multiple clinical trials have been unsuccessful in showing positive survival outcomes and biomarkers to select patients and monitor responses to novel targeted treatments have been lacking, not least because acquisition of tumour biopsies, especially during relapse after chemotherapy, is a substantial challenge. Liquid biopsies via blood sampling in SCLC, notably circulating tumour cells and circulating free tumour DNA can be readily and repeatedly accessed, and are beginning to yield promising data to inform SCLC biology and patient treatment. Primary cell cultures and preclinical mouse models can also be derived from the relatively plentiful SCLC circulating tumour cells providing a tractable platform for SCLC translational research and drug development.

Abstract B051: PDX-derived and patient-derived prostate cancer organoids as a clinically relevant platform for translational research

Abstract Metastatic castration-resistant prostate cancer (CRPC) is a genetically heterogeneous disease. Effective translational research demands a diverse and representative set of preclinical models. A major obstacle in the field is the limited capacity to culture prostate cancer-derived cells in vitro. Few cell lines exist. Those that are available do not well represent the genetic diversity of the disease, nor do they accurately predict in vivo response. Recently, organoid culture techniques developed in the Sawyers and Clevers laboratories have increased our ability to grow metastatic tumor-derived prostate cancer cells in vitro. This represents a great step forward, but is restricted by limited availability of tissue and a success rate of <20% when establishing new lines. In the field of prostate cancer, patient-derived xenograft (PDX) lines are a model that broadly represents the clinical and genetic diversity of the disease. Like primary prostate tumors, PDXs have not been readily adaptable to in vitro culture (including the standard organoid method), making them poorly suited for mechanistic studies or high-throughput drug screens. Therefore, there is great interest in adapting the prostate cancer PDX model to an in vitro culture system. The LuCaP series of PDXs is a well-characterized set of ~40 diverse prostate cancer specimens. Using LuCaP PDXs, we systematically tested several modifications to the organoid culture method. This includes the addition of factors to modify metabolism, growth, and differentiation; removal of standard media components; and combinations thereof. We show that p38 is required for growth and survival of almost all the LuCaP organoids. Removal of the p38 inhibitor component from standard prostate organoid media improves initial growth and makes it possible to maintain many PDX-derived organoids over several generations. Additional modifications to individual LuCaP culture conditions improve growth. We successfully cultured 21 of 24 different LuCaPs attempted, for at least one generation, and 10 have been grown long-term. We show that PDX-derived organoids recapitulate the phenotype of the original PDX tumor, including AR-dependent growth. For example, we have shown that homologous recombination deficient LuCaP organoid responses to olaparib reflect the enhanced sensitivity seen for patients in clinical trials. Additionally, our method improves the success rate for culturing samples directly from patient biopsies. We show that 2 of 3 biopsy-derived organoid lines that we have established grow well in our conditions but not in standard published conditions. The third grows equally well in both. Further, our data suggest that p38 is a previously unappreciated target for CRPC treatment. Importantly, our work immediately and significantly increases the number of prostate cancer lines available to the community by making the LuCaP PDXs accessible to in vitro culture, and by improving the success rate for establishing organoids directly from patient samples. Citation Format: Michael L. Beshiri, Caitlin M. Tice, Crystal Tran, Holly M. Nguyen, Adam G. Sowalsky, Supreet Agarwal, Keith H. Jansson, Kerry McGowen, Aian Neil Alilin, JuanJuan Yin, Fatima H. Karzai, William L. Dahut, Eva Corey, Kathleen Kelly. PDX-derived and patient-derived prostate cancer organoids as a clinically relevant platform for translational research [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B051.

Functional segregation of basal ganglia pathways in Parkinson's disease.

Dopamine exerts modulatory signals on cortex-basal ganglia circuits to enable flexible motor control. Parkinson's disease is characterized by a loss of dopaminergic innervation in the basal ganglia leading to complex motor and non-motor symptoms. Clinical symptom alleviation through dopaminergic medication and deep brain stimulation in the subthalamic nucleus likely depends on a complex interplay between converging basal ganglia pathways. As a unique translational research platform, deep brain stimulation allows instantaneous investigation of functional effects of subthalamic neuromodulation in human patients with Parkinson's disease. The present study aims at disentangling the role of the inhibitory basal ganglia pathways in cognitive and kinematic aspects of automatic and controlled movements in healthy and parkinsonian states by combining behavioural experiments, clinical observations, whole-brain deep brain stimulation fibre connectivity mapping and computational modelling. Twenty patients with Parkinson's disease undergoing subthalamic deep brain stimulation and 20 age-matched healthy controls participated in a visuomotor tracking task requiring normal (automatic) and inverted (controlled) reach movements. Parkinsonian patients on and off deep brain stimulation presented complex patterns of reaction time and kinematic changes, when compared to healthy controls. Stimulation of cortico-subthalamic fibres was correlated with reduced reaction time adaptation to task demand, but not kinematic aspects of motor control or alleviation of Parkinson's disease motor signs. By using clinically, behaviourally and fibre tracking informed computational models, our study reveals that loss of cognitive adaptation can be attributed to modulation of the hyperdirect pathway, while kinematic depends on suppression of indirect pathway activity. Our findings suggest that hyperdirect and indirect pathways, converging in the subthalamic nucleus, are differentially involved in cognitive aspects of cautious motor preparation and kinematic gain control during motor performance. Subthalamic deep brain stimulation modulates but does not restore these functions. Intelligent stimulation algorithms could re-enable flexible motor control in Parkinson's disease when adapted to instantaneous environmental demand. Our results may inspire new innovative pathway-specific approaches to reduce side effects and increase therapeutic efficacy of neuromodulation in patients with Parkinson's disease.

Abstract 2973: A comprehensive panel of patient-derived xenografts representing the molecular heterogeneity and diversity of triple-negative breast cancer

Abstract Purpose: Triple-negative breast cancer (TNBC) is a heterogeneous disease. Patients diagnosed with TNBC have a poor prognosis and identification of new biomarkers and therapeutic agents is a high priority. Patient-derived xenografts (PDX) are clinically relevant models that have emerged as important tool for the analysis of drug activity and predictive biomarker discovery. The purpose of this work was to analyze the molecular heterogeneity of a large panel of TNBC PDX with the perspective to test targeted therapy and to identify biomarkers of response. Experimental Design: PDX of early-stage TNBC established from 2003 to 2016 (N=60) were analyzed by high-resolution array CGH and gene expression profiling (Cytoscan HD and Human Gene 1.1 ST arrays). Subtypes were identified with the tool TNBCtype (Chen et al., 2012) based on transcriptomic data. A targeted next-generation sequencing (NGS) of 100 genes (the top frequently mutated genes in breast cancer) was performed on Illumina HiSeq2500 sequencer. COSMIC, Tumorportal and cBioportal databases were used for the interpretation of genomic variants. Immunohistochemistry (IHC) and morphologic analysis of PDX were performed as compared to the corresponding patients' tumors. PDX carrying targetable genomic alterations in the PI3K/AKT/mTOR and MAPK signaling pathways were treated by specific inhibitors (selumetinib, BAY 80-6946 and PF-04691502). Results: At the gene expression level, TNBC PDX represent all the different TNBC subtypes identified by the Lehmann classification. The frequency of the different TNBC subtypes was similar to the TGCA TNBC, except for the immunomodulatory subtype, underrepresented in PDX. Somatic pathologic mutations and copy number alterations were similar in PDX and TCGA TNBC patients. Among the top altered genes are TP53 and oncogenes and tumor suppressors of the PI3K/AKT/mTOR and MAPK pathways (including PIK3CA, AKT1, NF1 and NRAS/KRAS). At the histologic level, TNBC PDX were mainly composed of invasive ductal carcinoma of no special type, with some tumors being classified as apocrine or metaplastic carcinomas. Comparison with the original tumors show similar patterns (based on IHC analysis of CK5, CK8/18, CK14 and AR, FOXA1, EGFR and Ki67). In vivo efficacy experiments with PI3K and MAPK pathways inhibitors showed marked antitumor activity in PDX carrying genomic alterations of PIK3CA, AKT1 and NRAS, NF1 genes. Drug combination experiments are currently ongoing in PDX with simultaneous genomic alterations of PI3KCA and MAPK related genes. Conclusions: TNBC PDX reproduce the molecular heterogeneity and diversity of TNBC patients. This large collection of PDX is a clinically relevant platform for drug testing, biomarker discovery and translational research. Citation Format: Florence Coussy, Virginie Bernard, Marion Lavigne, Anais Boulai, Sophie Chateau-Joubert, Ahmed Dahmani, Elodie Montaudon, Cécile Reyes, Rania El Botty, Gaëlle Pieron, Cécile Laurent, Samia Melaabi, Anne Vincent Salomon, Ivan Bièche, Elisabetta Marangoni. A comprehensive panel of patient-derived xenografts representing the molecular heterogeneity and diversity of triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2973.

2140 Clinical and translational research (CTR) platform for undergraduate health sciences programs (UHSP) at University of Puerto Rico-Medical Sciences Campus (UPR-MSC) and Universidad Central del Caribe (UCC): Pipeline for students and faculty

OBJECTIVES/SPECIFIC AIMS: The University of Puerto Rico-Medical Sciences Campus and Universidad Central del Caribe, through the Title V Cooperative Project, devised a clinical and translational research (CTR) platform to pipeline students/faculty of undergraduate health sciences programs into CTR. Educational interventions in CTR—introductory intervention (II) and Annual Symposium (AS)—were designed to promote awareness, stimulate interest of students and faculty in CTR. METHODS/STUDY POPULATION: In the II the participants (n=159) were surveyed before and after a presentation and panel discussion about CTR. In addition, after the sessions—plenary, panel, and workshop—about CTR, the participants of AS (n=42) were surveyed for satisfaction and learning experience in CTR. RESULTS/ANTICIPATED RESULTS: Most participants of the II, 134 (84.3%) were students. In total, 58 (58, 36.5%) completed the post II survey. Of these, 53.4% satisfactorily defined the CTR concept Versus only 31.0% that could define CTR in the pre survey, 47 (81.7%) were unable to identify a CTR researcher and 45 (78.3 %) expressed interest in learning about CTR. In total, 28 (28, 66.7%) participants of the AS completed the satisfaction survey, out of which 17 (60.6%) were students. One hundred percent (100%) agreed that the AS served as a vehicle to increase their knowledge in CTR. DISCUSSION/SIGNIFICANCE OF IMPACT: The educational interventions demonstrated to be an effective strategy to promote awareness and stimulate interest of students and faculty in CTR. In addition, the results obtained, provided valuable baseline information for the planning—development of training cycles in CTR.

Bat-mouse bone marrow chimera: a novel animal model for dissecting the uniqueness of the bat immune system

Bats are an important animal model with long lifespans, low incidences of tumorigenesis and an ability to asymptomatically harbour pathogens. Currently, in vivo studies of bats are hampered due to their low reproduction rates. To overcome this, we transplanted bat cells from bone marrow (BM) and spleen into an immunodeficient mouse strain NOD-scid IL-2R−/− (NSG), and have successfully established stable, long-term reconstitution of bat immune cells in mice (bat-mice). Immune functionality of our bat-mouse model was demonstrated through generation of antigen-specific antibody response by bat cells following immunization. Post-engraftment of total bat BM cells and splenocytes, bat immune cells survived, expanded and repopulated the mouse without any observable clinical abnormalities. Utilizing bat’s remarkable immunological functions, this novel model has a potential to be transformed into a powerful platform for basic and translational research.

ETRIKS platform: Conception and operation of a highly scalable cloud-based platform for translational research and applications development

We describe the genesis, design and evolution of a computing platform designed and built to improve the success rate of biomedical translational research. The eTRIKS project platform was developed with the aim of building a platform that can securely host heterogeneous types of data and provide an optimal environment to run tranSMART analytical applications. Many types of data can now be hosted, including multi-OMICS data, preclinical laboratory data and clinical information, including longitudinal data sets. During the last two years, the platform has matured into a robust translational research knowledge management system that is able to host other data mining applications and support the development of new analytical tools.

Integrated clinical and genomic data platform for translational research and precision medicine

Integrated clinical and genomic data platform for translational research and precision medicine

State of the Journal: CMGH ’s Progress, Prospects, and Impact Factor

State of the Journal: CMGH ’s Progress, Prospects, and Impact Factor

Patient-derived xenograft in zebrafish embryos: a new platform for translational research in gastric cancer

BackgroundGastric cancer (GC) is among the most commonly cancer occurred in Asian, especially in China. With its high heterogeneity and few of validated drug targets, GC remains to be one of the most under explored areas of precision medicine. In this study, we aimed to establish an in vivo patient-derived xenograft (PDX) model based on zebrafish (Danio rerio) embryos, allowing for a rapid analysis of the angiogenic and invasive potentials, as well as a fast drug sensitivity testing.MethodsTwo human gastric cancer cell lines (AGS and SGC-7901) were xenografted into zebrafish embryos, their sensitivity to 5-FU were tested both in vitro and in vivo. Fourteen human primary cells from gastric cancer tissue were xenografted into zebrafish embryos, their proliferating, angiogenic and metastatic activities were evaluated in vivo. Sensitivity to 5-FU, docetaxel, and apatinib were also tested on primary samples from four patients.ResultsSGC-7901 showed higher sensitivity to 5-FU than AGS both in vitro (6.3 ± 0.9 μM vs.10.5 ± 1.8 μM) and in vivo. Nine out of fourteen patient samples were successfully transplanted in zebrafish embryos and all showed proliferating, angiogenic and metastatic potentials in the living embryos. Four cases showed varied sensitivity to the selected three chemotherapeutic drugs.ConclusionsOur zebrafish PDX (zPDX) model is a preclinically reliable in vivo model for GC. The zPDX model is also a promising platform for the translational research and personalized treatment on GC.

Patient-Derived Bladder Cancer Xenografts.

Patient-derived xenograft (PDX ) tumors are models developed by direct transplant of human tumors into immune-compromised hosts such as nude mice. These models retain the histological and genetic characteristics of the primary tumor and are considered a valuable platform for translational cancer research. This chapter describes the methodology to establish and propagate bladder cancer PDX model.

Development and Applications of Patient-Derived Xenograft Models in Humanized Mice for Oncology and Immune-Oncology Drug Discovery.

With the recent approval of four novel immune oncology agents for the treatment of various cancers, the emerging power of this drug class has been substantiated. However, the full potential of such agents is yet to be realized, with only a fraction of the patient population responding to these drugs. A more advanced pre-clinical and translational research platform may increase our understanding of the mechanisms associated with immune-mediated cancer cell death, thereby facilitating the design and development of more generally efficacious agents and drug regimens. Described in this report are the nuances, advantages, and limitations of such a research approach. © 2017 by John Wiley & Sons, Inc.